The NOTCH signaling pathway has been identified as playing an important role in many diverse biological functions, including differentiation, and cellular proliferation (see U.S. Pat. No. 6,703,221). Mutations that increase NOTCH signaling have been associated with the development of leukemia and inhibitors of NOTCH are being studied for their potential use in the treatment of neurological diseases and cancer (Artavanis-Tsakonas, et al., Science. 284:770-776 (1999); Wang, et al., Science 306:269-271 (2004); Stockhausen, et al., Br. J. Cancer 92:751-759 (2005); Van Es, et al., Nature 435:959-963 (2005)).
The NOTCH pathway is activated by four different transmembrane receptor subtypes (designated as NOTCH-1-NOTCH-4) that rely upon regulated proteolysis. Expression patterns of NOTCH depend on cell type. Following ligand binding, the receptor undergoes sequential cleavage by metalloproteases of the ADAM family (Bru, et al., Mol. Cell 5:207-216 (2000); Mumm, et al., Mol. Cell. 5:197-206 (2000)) and the presenilin-dependent gamma-secretase (Selkoe, et al., Annu. Rev. Neurosci. 26:565-97 (2003); De Strooper, et al., Nature 398:518-522 (1999)). The final proteolytic cleavage step permits the intracellular domain of the NOTCH receptor to translocate to the cell nucleus where it interacts with transcription factors to induce target gene expression.
In the cell nucleus, the NOTCH intracellular domain undergoes ubiquitilation. Proteolytic processing of the NOTCH precursor protein by furin-protease and its trafficking to the cell membrane also determine turnover and availability of receptors, and, in turn, activation of this signaling pathway. Altered glycosylation of the Notch extracellular domain by Fringe protein family members may also modify efficiency of ligand binding.
As mentioned above, inhibitors of NOTCH, particularly gamma-secretase inhibitors, have received a great deal of attention as possible therapeutic agents for the treatment of neurological diseases (especially Alzheimer's disease) and cancer (especially leukemia). Additional therapeutic uses for agents that alter the NOTCH signaling pathway would be of clear interest to companies developing therapeutic agents in this area and to clinicians.